Antibody directed enzyme prodrug therapy (ADEPT) aims to improve the selectivity of cytotoxic drugs. An enzyme is employed which acts to convert a prodrug to an active drug. The action of the drug is localised to the site of interest through use of an antibody which binds to a tumour associated antigen. This antibody is conjugated to, or formed as a fusion protein with, the enzyme which acts on the prodrug thus ensuring prodrug conversion occurs predominantly at the site of interest.
The therapeutic efficiency and specificity of ADEPT systems have, however, been limited by conversion of prodrug in normal tissues, due to residual enzyme-antibody conjugate and leakage of the conjugate from the tumour (which can be due to loss of the antigen from the tumour cells into the circulation). In an attempt to address this issue, an enzyme clearance stage has been developed to remove residual enzyme activity and thus minimize side-effects of the therapy. This has relied upon a further antibody that binds to the enzyme. This antibody is glycosylated to facilitate clearance via the liver (1).
US 2003-0068322 (Hansen) describes antibody based clearing agents to effect clearance of circulating targeting protein-enzyme conjugate. In one embodiment, the clearing agent binds to the enzyme. However, the clearing agent binds at a site that does not interfere with enzyme activity. WO 96/40245 and U.S. Pat. No. 5,958,408 represent similar disclosures.
Napier et al—Clinical Cancer Research Vol. 6, 765 to 772, March 2000—describes a clinical trial in which ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme pro drug therapy with A5B7 F(ab′)2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). In this trial, a galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. Napier states that a human anti-mouse antibody response (HAMA) was found in all patients after two weeks preventing further therapy (see page 768 second column under the heading immune response). Napier suggest that immunosuppressive agents may be utilised in order to facilitate the use of such clearing agents in the context of ADEPT therapy.
WO 91/17761 describes a technique distinct from the ADEPT technique. In this technique, an antagonist is targeted to normal cells to enable the cytotoxin to be used therapeutically to treat only the diseased cells. Thus, the method aims to protect normal cells.
EP0308208 relates to antibodies and antibody conjugates modified by conjugation to glycoside residues that bind to the human hepatic asialoglycoprotein receptor to enable rapid clearance from the circulation.
EP0733072 and U.S. Pat. No. 5,876,691 describe antibodies specific for carcinoembryonic antigen (CEA).